Reactive Arthritis (ReA) is an inflammatory arthritis that arises after certain genitourinary and gastrointestinal infections. Chlamydia trachomatis (Ct) is a known trigger for ReA. Ct has been proven to exist in a persistent metabolically active state that is very different than the active infection. Paramount in this persistence is the up-regulation of certain Ct heat shock protein 60 (HSP-60) paralog genes. Persistent Ct has been demonstrated by polymerase chain reaction (PCR) in the synovial tissue of patients with ReA years after their initial exposure. Our long-term objective is to establish definitive proof that Ct-induced ReA can be cured with prolonged combined antimicrobial therapy. It is our hypothesis that treatment with a combination of antibiotics, which also inhibits Ct HSP-60 production, can eradicate this persistent Chlamydial state; thereby curing chronic Ct-induced ReA. Rifampin has been shown to attenuate Ct HSP production; it also displays synergistic effect with azithromycin in Ct infections. Our proposal has two aims that will be accomplished with 1) an in vivo therapeutic clinical trial, and 2) a concurrent in vivo study. 1. In the therapeutic clinical trial, we expect to establish proof that significantly more patients respond to prolonged, combined antimicrobial therapy compared to placebo. Patients with probable Ct-induced ReA will be screened with a peripheral blood mononuclear cell (PBMC) and synovial biopsy PCR for Chlamydia. If either PCR is positive, they will be enrolled in this double-blind trial and randomized to one of three treatment groups: doxycydine and rifampin, azithromycin and rifampin, or placebo. All patients will be treated for 9 months and followed regularly with clinical assessments to determine if they are responders. 2. Our in vitro study aims to prove that PBMC's infected with persistent Ct can be cleared of their infection with the same combination of antibiotics. The PBMC's will be obtained from normal controls (infected in vitro) and patients in our therapeutic trial. We will also show that infected PBMC's from symptomatic patients respond to the antimicrobials exactly as the normal controls that are infected in vitro. This project will be a critical pathway in discovering a cure for persistent Chlamydia infections in the joint and at other anatomic sites. Chronic Chlamydia infections have also been linked to trachoma, tubal infertility, coronary artery disease, asthma, certain types of cervical cancer, and possibly other diseases. [unreadable] [unreadable] [unreadable]